RNAi is antagonized by A→I hyper‐editing

RNA interference (RNAi) and adenosine to inosine conversion are both mechanisms that respond to double-stranded RNA (dsRNA) and have been suggested to have antiviral roles. RNAi involves processing of dsRNA to short interfering RNAs (siRNAs), which subsequently mediate degradation of the cognate mRNAs. Deamination of adenosines changes the coding capacity of the RNA, as inosine is decoded as guanosine, and alters the structure because A-U base pairs are replaced by I*U wobble pairs. Here we show that RNAi is inhibited if the triggering dsRNA is first deaminated by ADAR2. Moreover, we show that production of siRNAs is progressively inhibited with increasing deamination and that this is sufficient to explain the inhibition of RNAi upon hyper-editing of dsRNAs.